Phenanthrene, but not its isomer anthracene, effectively activates both human and mouse nuclear receptor constitutive androstane receptor (CAR) and induces hepatotoxicity in mice.
Phenanthrene, but not its isomer anthracene, effectively activates both human and mouse nuclear receptor constitutive androstane receptor (CAR) and induces hepatotoxicity in mice.
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DOI：
10.1016/j.taap.2019.114618
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发表时间：
2019-09
影响因子：
3.8
通讯作者：
Han Yang;Zhe Shi;Xiao-Xiao Wang-Xiao;Rong-chuan Cheng;Min Lu;Jiayin Zhu;Wenhai Deng;Yuyao Zeng;Li-yang Zhao;Shu-Yun Zhang
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文献类型：
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作者：
Han Yang;Zhe Shi;Xiao-Xiao Wang-Xiao;Rong-chuan Cheng;Min Lu;Jiayin Zhu;Wenhai Deng;Yuyao Zeng;Li-yang Zhao;Shu-Yun Zhang
多环芳烃（PAHs）是一类普遍存在的全球性环境污染物，对人类健康产生不利影响。在多环芳烃中，菲和蒽是由三个苯环组成的异构体。在本研究中，我们比较了这两种异构体对组成型雄甾受体（CAR）的激活和对肝脏的毒性作用。在HepG2细胞和人原代肝细胞中，菲显著诱导人药物代谢酶mecyp2b6启动子活性和基因表达，而蒽不显著。菲能显著提高CYP2B10的表达水平，引起小鼠肝毒性，而蒽则没有。菲在野生型小鼠肝脏中诱导CAR的核积累，但在CAR - / -小鼠中没有。在菲暴露的野生型小鼠中发现肝细胞坏死，一些CAR相关基因如CYP2B10、CYP3A11、UGT1A1、SULT2A1和GSTM3的表达水平升高，肝谷胱甘肽水平降低，而CAR- / -小鼠则没有。此外，在生羊肉和烤羊肉样品中均检测到菲和蒽。这些样品中菲的平均浓度远高于蒽。本研究首次证明，菲而非其同分异构体蒽能有效激活人和小鼠核受体CAR，而CAR在菲诱导的小鼠肝毒性中起着至关重要的作用。与蒽相比，K区可能是菲活化CAR的重要电子结构。多环芳烃污染食品的膳食摄入是人类重要的暴露途径。接触菲可影响人体健康，尤其是与肝脏有关的健康。
Polycyclic aromatic hydrocarbons (PAHs) are a class of pervasive global environmental pollutants and adversely affect human health. Among PAHs, phenanthrene and anthracene are isomers consisting of three benzene rings. In the present study, we have made comparisons of constitutive androstane receptor (CAR) activation and toxic effects on the liver between these two isomers. Phenanthrene, but not anthracene, significantly induced promoter activity and gene expression of human drug metabolizing enzymeCYP2B6in HepG2 cells and human primary hepatocytes, respectively. Phenanthrene, but not anthracene, significantly increased CYP2B10 expression levels and caused hepatotoxicity in mice. Phenanthrene induced the nuclear accumulation of CAR in the liver of wild-type mice, but not CAR−/−mice. Hepatocellular necrosis, elevated expression levels of some CAR-related genes such as CYP2B10, CYP3A11, UGT1A1, SULT2A1 and GSTM3, and lower hepatic glutathione levels were found in phenanthrene-exposed wild-type mice but not CAR−/−mice. Additionally, phenanthrene and anthracene were detected in both raw and grilled lamb samples. The average concentrations of phenanthrene were much higher than those of anthracene in these samples. This study is the first to demonstrate that phenanthrene, but not its isomer anthracene, effectively activates both human and mouse nuclear receptor CAR, and CAR plays a crucial role in phenanthrene-induced mouse hepatotoxicity. Compared with anthracene, K region may be an important electronic structure of phenanthrene for activation of CAR. Dietary consumption of PAHs-contaminated food is an important exposure route for humans. Exposure to phenanthrene may affect human health especially associated with liver.